APPLICANT'S ABSTRACT: Independent Scientist Award-KO2: As Co-Director of an Alcoholism Research Center, I have supported my salary since 1991. In July, 1998, the VA will terminate this national program. At that time, I will assume substantial clinical responsibilities unless I find an alternative mechanism to support my salary. This K02 Award would enable me to sustain my research and develop further expertise in areas critical to my research program. My research has focussed on characterizing the clinical significance of glutamate and GABA dysregulation in alcoholism. With NIAAA support, I conducted a study that indicated that the NMDA antagonist, ketamine, had ethanol-like effects and altered reward valence in alcoholic patients. These patients showed blunted dysphoric responses and increased euphoric responses. Thus, NMDA receptor dysregulation may alter the NMDA antagonist component of ethanol response in patients in a manner that promotes relapse. To build towards pharmacotherapy, I have proposed to compare responses to a partial agonist of the strychnine-insensitive glycine (SIGLY) site of the NMDA receptor in recently detoxified alcoholics and controls (Years 1-3) and to determine whether drugs acting at this site modulate ethanol cue-induced craving in patients (Years 4-5). To facilitate these objectives, I will pursue additional training in multivariate statistics and I will work collaboratively to develop methods for assessing craving that are independent of self-report and would be applied to studies in Years 4-5. My other major research focus has been the study of reductions in GABA function in alcoholics using 133I iomazenil single photon emission computerized tomography (SPECT) and magnetic resonance spectroscopy (lH-NMR). Respectively, these techniques measure benzodiazepine/GABA-A receptor density and GABA levels. I have proposed a study that employs both SPECT and 1H-NMR in a longitudinal assessment of the recovery of GABA systems with sobriety. If funded, this study would cover years 1-4 of this K02 period. In year 5, I propose to characterize the activity of the GABA synthetic enzyme, glutamic acid decarboxylase, in alcoholic patients using a 13C-glucose infusion technique. In this work, I focus my career development on gaining further expertise in 1H- and 13C-NMR. As a result, I have developed an educational program designed to facilitate my development in these areas. In summary, this K02 award would foster my academic development and enable me to better contribute to the building of pathophysiologic models of alcoholism that can guide medications development for this disorder.